U.S. Pat. No. 4,316,839; U.S. Pat. No. 4,352,817; U.S. Pat. No. 4,386,028; U.S. Pat. No. 4,352,816;
U.S. Pat. No. 4,352,818; U.S. Pat. No. 4,353,827; and U.S. Pat. No. 4,489,003 disclose the compounds used for the novel treatment of the present invention. In above U.S. patents the compounds are disclosed as benzodiazepine receptor ligands with antagonistic to agonistic intrinsic activity at the benzodiazepine receptor site, as well as chemical intermediates for such compounds.
Guy de Bonnel et al. in European Journal of Pharmacology 93. 45-54 (1983) disclose that two benzodiazepine (lorazepam and diazepam) agonists selectively antagonize the excitatory activation produced by kainate (an excitatory amino acid (EAA) agonist). However, it is clearly demonstrated therein that the effects of lorazepam and diazepam are benzodiazepine effects which can be antagonized by benzodiazepine receptor antagonists. One of the compounds of formula I below, namely Ro 15-1788 which is identical to the first compound of the table below, was used by Bonnel et al. to demonstrate that the reversal of the excitatory activation produced by kainate was actually mediated through the benzodiazepine receptors rather than through an EAA receptor. Ro 15-1788 is disclosed by Bonnel et al. to antagonize the kainate antagonist response produced by lorazepam and diazepam, as mediated through the benzodiazepine receptor.
The excitatory amino acid receptors (EAA receptors) and their clinical importance are well described (for example Povl Krogsgaard-Larsen, Amino Acid Receptors in Comprehensive Medicinal Chemistry edited by Corwin Hansch et al., Pergamon Press 1990, Vol. 3, p. 493-537 and Michael B. Robinson and Joseph T. Coyle, FASEB J. 1, 446-455 (1987). It is generally recognized that glutamate is an endogenous ligand for all subtypes of EAA receptors, and that aspartate probably also acts as a neurotransmitter for all types of such receptors so far detected. Quisqualate/AMPA (AMPA is .alpha.-amino-3-hydroxy-5-methylsoxazole-4-propionate) receptors, NMDA (NMDA is N-methyl-D-aspartate) receptors and kainate receptors for examples are recognized as EAA or glutamate subreceptors. Compounds that act unselectively at all subreceptor types are known, and compounds that act more selectively at one or two subreceptor types are known. Among the clinical diseases which may be treated by administration of EAA antagonists Huntington's disease, Alzheimer's disease, psychosis, and schizophrenia can be mentioned. Further the neurodegenerative events following anoxia, ischemia, migraine and epilepsia may be mentioned.